Abstract

Objectives This study sought to determine the association between markers of cardiomyocyte injury in ambulatory subjects and sudden cardiac death (SCD).

Background The pathophysiology of SCD is complex but is believed to be associated with an abnormal cardiac substrate in most cases. The association between biomarkers of cardiomyocyte injury in ambulatory subjects and SCD has not been investigated.

Methods Levels of cardiac troponin T, a biomarker of cardiomyocyte injury, were measured by a highly sensitive assay (hsTnT) in 4,431 ambulatory participants in the Cardiovascular Health Study, a longitudinal community-based prospective cohort study. Serial measures were obtained in 3,089 subjects. All deaths, including SCD, were adjudicated by a central events committee.

Sudden cardiac death (SCD) is a major public health problem (1,2). Over the past few decades, improvements in primary and secondary prevention measures have led to significant declines in cardiovascular mortality from coronary heart disease (3,4). However, the rates of SCD have declined to a lesser extent (5–8), which emphasizes the need for a better understanding of SCD epidemiology and risk factors.

The pathophysiology of SCD is complex, but it is generally believed that an abnormal cardiac substrate underlies most cases (2,9–11). The association of cardiomyocyte injury and SCD risk in the general population has not been studied to date. Such investigation could have been limited by the inability of conventional assays to detect very low levels of circulating troponins that would reflect subclinical cardiomyocyte damage.

A recently developed highly sensitive cardiac troponin T assay (12) has allowed detection of very low levels of circulating troponin, even in ambulatory asymptomatic subjects (12,13). This biomarker of cardiomyocyte injury has been found to be associated with adverse cardiovascular outcomes, including heart failure and cardiovascular mortality (14–17).

We hypothesized that cardiomyocyte injury, assessed by measures of cardiac troponin T levels by a highly sensitive assay (hsTnT), is associated with SCD risk beyond traditional risk factors. The study hypothesis was tested in a large prospectively followed community-based population.

Methods

Study population

The CHS (Cardiovascular Health Study) is a longitudinal study of adults age 65 years or older at recruitment. The rationale, design, and methods of CHS, including information on data collection and definition of comorbid conditions have been previously published (18,19). Briefly, the CHS population consisted of 5,888 men and women recruited from Medicare files from 4 communities in the United States (Forsyth County, North Carolina; Sacramento County, California; Washington County, Maryland; and Pittsburgh, Pennsylvania). The original cohort of participants included 5,201 subjects who were enrolled from 1989 to 1990. A minority cohort was enrolled between 1992 and 1993, which included 687 African Americans. The cohort for current analysis included 4,431 participants who had baseline levels of hsTnT from sera collected at enrollment. Of those, 3,089 participants had follow-up measures (2 to 3 years after the original assay) and were included in analyses of the association between change in hsTnT levels and SCD risk (Fig. 1). The CHS was approved by the institutional review boards at the University of Washington (Seattle, Washington) and participating sites. All subjects gave written informed consent at time of enrollment.

Initial assessment, follow-up, and cardiovascular events

At enrollment, study participants were assessed by a standardized questionnaire that addressed variable health and behavioral risk factors, in addition to a physical examination (19,20). For each cardiovascular condition, self-reports were confirmed by components of the baseline examination or, if necessary, by a validation protocol that included either review of medical records or surveys of treating physicians (19). For instance, in addition to patient interviews, the baseline examinations sought to identify major Q waves or the combination of minor Q waves and ST-T-wave changes on electrocardiograms to confirm self-reported myocardial infarction (MI). Self-reported heart failure was confirmed by symptoms, physical signs, and the use of both diuretics and either digitalis or a vasodilator. Further confirmation of MI or heart failure, was sought from treating physicians by questionnaire or from hospitals by discharge summaries, as well as by review of medical records (19). Coronary heart disease was defined as a history of angina, coronary revascularization, or previous MI. After the initial assessment, enrolled subjects were contacted every 6 months for follow-up, alternating between telephone interviews and clinic visits through 1998 and 1999 and by telephone interviews only thereafter. All participants had resting 12-lead electrocardiograms obtained at baseline, and these were repeated annually through the last clinic visit. Echocardiograms were obtained at baseline for the original cohort and at the study visit in 1994 and 1995 for both cohorts. In addition, discharge diagnoses for all hospitalizations were collected. New cardiovascular events, reported during a clinical visit, a telephone encounter, or from a hospital stay were confirmed by obtaining medical records and adjudicated by a centralized events committee (20). The details on ascertainment and adjudication of death and cardiovascular events, including incident heart failure and MI, in CHS have been previously published (20). Incident heart failure was confirmed by documentation in the medical record of a constellation of symptoms and physical signs with supporting clinical findings or a record of medical therapy for heart failure. Incident MI was confirmed by electrocardiographic criteria and measures of cardiac enzymes (20). Information on death was obtained from reviews of medical records, death certificates, autopsy reports, and coroners’ reports; ascertainment of death was 100%. Causes of death were assessed by additional reviews of inpatient, nursing home, or hospice records; physician questionnaires; and interviews with next of kin. Autopsy reports were also reviewed when available. Cardiovascular mortality was defined as mortality related to atherosclerotic heart disease, mortality following cerebrovascular disease, or mortality from other atherosclerotic and cardiovascular diseases including heart failure (20).

To identify SCD cases for the present study, all cases of fatal cardiovascular death were reviewed and adjudicated by physicians. SCD was defined as a sudden instantaneous pulseless condition, presumed to be from a malignant ventricular arrhythmia, in a previously stable individual without evidence of a noncardiac cause of the arrest. We a priori sought to exclude cases with nonarrhythmic characteristics, including those with evidence of progressive hypotension or advanced congestive heart failure before death. All SCD events in this analysis occurred out of the hospital or in the emergency room. All deaths that occurred under hospice or nursing home care or in subjects with life-threatening noncardiac comorbidities were not considered SCD. Available data from death certificates, informant interviews, physician questionnaires, coroner’s reports, and hospital discharge summaries were reviewed, as well as circumstances surrounding the event, to accurately classify whether the subject had experienced SCD. For nonwitnessed deaths, the participant must have been seen within 24 h of the arrest in a stable condition and without evidence of a noncardiac cause of cardiac arrest. A blinded second physician review of a random sample of 70 of these death records showed an 88% inter-reviewer agreement and kappa = 0.74 for SCD (21).

Cardiac troponin T assays

Details on blood sample acquisition as well as analytical and quality assurance methods in CHS were previously published (22). All measurements of TnT levels were performed in a central blood analysis laboratory. Baseline measures were obtained from sera collected at enrollment. Follow-up measures were performed on blood samples collected 2 to 3 years later. Blood samples were stored at –70°C to –80°C and thawed just prior to laboratory assays (maximum of 3 freeze-thaw cycles) in April 2010. All cardiac TnT concentrations were measured using highly sensitive TnT reagents on an Elecsys 2010 analyzer (Roche Diagnostics, Indianapolis, Indiana). The analytical measurement range of the assay was 3 to 10,000 pg/ml with an analytical coefficient of variation of 10% (12). Values of hsTnT that were below the threshold of detection were set to 2.99 for continuous analyses. The analytical sensitivity, specificity, interferences, and precision of the assay were previously validated (12). The value at the 99th percentile cutoff from a healthy reference population was 13.5 pg/ml (12). The hsTnT measurements for this study are from reagent lots not affected by the recent technical bulletin from Roche Diagnostics regarding calibration curves of the assay for some TnT prior reagent lots (23). All technologists performing and recording the biomarker assay results were blinded to participants’ outcomes including SCD.

Statistical analyses

The risk of SCD as a function of baseline hsTnT levels was assessed in the overall population. Furthermore, the association of change in hsTnT level with SCD was assessed in a group of participants with serial measures. Plasma levels of hsTnT were analyzed both as continuous variables for which natural log–transformed values were used, as well as categorized into 3 groups of low, intermediate, and high risk based on their association with SCD. The characteristics of these groups were compared by using the chi-square test for proportions, the analysis of variance method for normally distributed continuous variables, and the Kruskal-Wallis test for non-normally distributed continuous variables. Statistical analyses were performed using JMP Pro (version 9.0, SAS Institute, Cary, North Carolina) and STATA (version 12.1, StataCorp, College Station, Texas). We considered p values of <0.05 statistically significant.

The study hypothesis of the association between hsTnT levels and SCD risk was first tested with hsTnT levels analyzed as a continuous variable. The 3 groups were subsequently identified by using Cox proportional hazards analyses of SCD risk in participants with undetectable levels of hsTnT (n = 1,442) and deciles of the population with detectable levels (n = 2,989) (Fig. 2). The risk of SCD with increasing deciles of detectable hsTnT levels compared with that for participants with undetectable levels was employed to identify the low-risk group. The cutoff was defined by the decile above which there was a statistically significant increase in SCD risk compared with that for participants in lower deciles and undetectable levels group. The high-risk group was defined by evaluating SCD risk with descending deciles of detectable hsTnT levels compared with that of the 10th decile. The cutoff was defined by the decile below which there was a statistically significant decrease in SCD risk compared with that for participants in upper deciles. Kaplan-Meier curves were used to present cumulative SCD in the previously defined groups (log-rank test used for comparison).

Analysis was performed to define low- (≤5.00 pg/ml), intermediate- (5.01 to 12.09 pg/ml), and high- (≥12.10 pg/ml) risk categories of sudden cardiac death (SCD) based on Troponin T levels by a sensitive assay (hsTnT). Hazard ratios (95% confidence intervals) of SCD with increasing deciles (D1 to D10) of detectable hsTnT levels are compared with those for subjects with undetectable levels (≤2.99 pg/ml). ∗Refers to undetectable levels to hsTnT.

Covariate-adjusted Cox models were employed to study the association of baseline hsTnT levels and SCD risk. The first set of multivariable analyses adjusted for demographics and baseline factors found to have a statistically significant relationship with SCD in univariate analyses. These factors included: age; race (African American vs. not); sex; smoking (current vs. former vs. never); physical activity (log-transformed kilocalories per day); previous diagnoses of heart failure, coronary disease, MI, stroke or transient ischemic attack; ventricular conduction delay; Q and QS abnormalities; prolonged QT interval; qualitative left ventricular ejection fraction (<45% vs. 45% to 55% vs. >55%); left ventricular mass by electrocardiogram; systolic blood pressure; serum glucose levels; serum total and high-density lipoprotein cholesterol levels; estimated glomerular filtration rate (by the modified diet in renal disease formula); C-reactive protein (log-transformed); N-terminal pro–B-type natriuretic peptide (log-transformed); and use of aspirin, antihypertensives, antiarrhythmics and digoxin. Further details about these covariates are included in the Online Table. The second set of multivariable analyses additionally adjusted for incident heart failure and MI, in a time-dependent analysis, to account for the well-established relationship between these conditions and SCD. Hazard ratios (HRs) and their 95% confidence intervals (CIs) are reported from the proportional hazards models.

The association between change in hsTnT levels and SCD risk was evaluated in Cox models as discussed previously. The change in hsTnT levels was analyzed as a continuous variable of change per years between measurements from baseline and adjusted for baseline levels in multivariable models.

Finally, given that sudden and nonsudden cardiovascular deaths may have similar myocardial or coronary substrates, we provide parallel analyses with endpoints of all-cause mortality and nonsudden cardiovascular death.

Results

Based on the associations of deciles of hsTnT and SCD, hsTnT was categorized into 3 groups with cutoff points at 5.01 and 12.09 pg/ml. The demographics and clinical characteristics of the overall study population (n = 4,431) and by hsTnT category are summarized in Table 1. Participants were 72.8 ± 5.6 years of age at enrollment (range 65 to 100), 40.8% were men, and 16.3% were African Americans. Most of participants (91%) had preserved left ventricular function (ejection fraction >55%). Overall, higher levels of hsTnT were associated with prevalent cardiovascular disease and risk factors (Table 1). There were 69 (3.4% of 2,039), 99 (6.6% of 1,498), and 78 (8.7% of 894) cases of SCD in the low-, intermediate-, and high-risk categories. The cumulative hazard of SCD by hsTnT category in the overall population is shown in Figure 3 (log-rank test p value <0.0001).

Finally, there was a significant association between baseline levels of hsTnT and the risk of all-cause mortality (HR for +1 log[hsTnT]: 1.15, 95% CI: 1.07 to 1.23, p = 0.0001] and nonsudden cardiovascular death (HR for +1 log[hsTnT]: 1.16, 95% CI: 1.02 to 1.30, p = 0.02), which persisted in covariate-adjusted models accounting for baseline risk factors, as well as incident MI and heart failure (Table 4). Similarly, these associations were also observed with analyses of serial measures and change of hsTnT levels from baseline (Table 4).

Discussion

In a large community-based population followed for up to 17 years, there was a significant graded association between cardiac TnT levels measured by a highly sensitive assay and long-term risk of SCD. The Kaplan-Meier curves for cumulative SCD, based on hsTnT levels, separated very early after enrollment and continued to diverge throughout the duration of the study. The association between hsTnT levels and SCD risk persisted in covariate-adjusted analyses accounting for an extensive number of risk factors including low ejection fraction, incident heart failure, and MI, suggesting that cardiomyocyte injury increases SCD risk beyond the effect of these covariates. Finally, there was a significant association between changes in hsTnT levels and SCD risk even after adjustment for covariates denoting a dynamic change in risk, which can be assessed with serial measures.

The findings are novel and have significant clinical implications. Cardiac troponins are the preferred biomarkers for the diagnosis of acute MI (24). Elevated levels of these biomarkers may also be observed in other acute clinical circumstances, in which myocardial injury may occur, and represent an indicator of poor outcomes (25,26). The prognostic value of such elevations has been also increasingly recognized in chronic cardiac conditions, such as stable coronary disease and heart failure (27,28). In the general population, detectable levels of cardiac troponins by conventional assays have been associated with structural heart disease (29) and increased risk of adverse cardiovascular events and cardiac mortality (30–32). However, the detection thresholds of these assays have limited the application of such findings for clinical risk stratification purposes (29).

The recently available hsTnT assay has allowed detection of much lower concentrations of circulating TnT (12) and was found to have improved accuracy for the diagnosis of MI compared with conventional assays (33). More recent studies have suggested that this assay may have potential beyond MI diagnosis and may provide important information regarding cardiovascular risk in various populations (14–17). In patients with stable coronary disease and those with chronic heart failure, circulating hsTnT levels have been linked to cardiovascular mortality (14,15). In the general population, cardiac troponin levels by a highly sensitive assay were found to be associated with structural heart disease and traditional cardiovascular risk factors (16,17), but they provided independent prognostic information regarding incident heart failure and cardiovascular and all-cause mortality (16,17). The current study extends these observations to SCD risk in the general population of older adults. This population is of particular interest given that it contributes most of the SCD cases to the community (2,34,35).

The pathophysiological mechanisms underlying the associations observed in this study deserve further investigation. It is possible that cardiomyocyte injury in ambulatory subjects results in myocardial scarring, providing an anatomical substrate for electrical reentry and lethal arrhythmias. Such injury could be related to aging, clinically recognized disease states (16), or subclinical conditions such as unrecognized coronary disease. In fact, coronary artery disease underlies a significant subset of SCD cases (2,9). It is possible that many SCD victims develop myocardial ischemia prior to their collapse, but in contrast to those who present to the emergency rooms with acute coronary syndromes, SCD victims experience a sudden circulatory collapse—most commonly from a life-threatening arrhythmia. The myocardial or coronary substrates of such events may be similar to those of nonsudden cardiovascular deaths. In fact, baseline and serial measures of hsTnT in this study were found to be associated with all-cause mortality and nonsudden cardiovascular deaths as well, suggesting an overlap in the pathophysiological mechanisms leading to sudden and nonsudden cardiovascular deaths. HR for SCD as a function of baseline hsTnT levels appeared to be higher than those for all-cause mortality and nonsudden cardiovascular death. CI, however, overlapped, which precludes definitive conclusions regarding strength of associations with SCD compared with all-cause and nonsudden cardiovascular mortality. Importantly, hsTnT levels were associated with SCD events that occurred up to 17 years after the initial assay. These observations, along with our observations of an association between change in hsTnT levels and SCD, suggest that cardiac troponin levels in ambulatory subjects may reflect an ongoing myocardial injury–remodeling process that may result in structural cardiac abnormalities that may in turn pre-dispose to SCD. These explanations are, however, hypothetical and further research would be required to address the mechanisms underlying these associations.

Study limitations

The purpose of this paper was to study the association between cardiomyocyte injury assessed by hsTnT levels and the risk of SCD. The highlight was meant to be on the biological associations that help to better understand SCD. We did not aim to build a risk prediction model. Given the multifactorial nature of SCD and the complex pathology, no diagnostic test exists. The incidence of the outcome is relatively low and troponins are detected in a significant proportion of the population, which limits the use of this biomarker for diagnostic purposes. Nonetheless, a risk prediction model would require methods that are totally different than the methods employed in this paper. Also, the predictive value of hsTnT for SCD risk stratification purposes needs to be formally assessed and the findings need to be replicated in a different cohort before these could be applied in clinical practice.

The study has the inherent limitations of observational studies, and the findings, therefore, may have been affected by residual confounding and do not establish causality. Also, no formal workup to rule out myocardial ischemia was performed and subclinical coronary artery disease could have been the underlying pathology. However, the associations persisted after adjusting for an extensive number of covariates and traditional risk factors that are usually assessed in clinical practice as well as incident heart failure and MI, suggesting that cardiomyocyte injury may be involved in a pathophysiological process, which may lead to sudden death independent of these conditions. Another limitation was that blood samples were available for hsTnT assays in approximately 75% of the CHS population, which could have introduced a bias in the overall estimates of SCD. However, this does not negate the findings of significant association between these levels and SCD. The observations were made in a population of older adults and, therefore, may not be generalized to younger populations. Finally, there is no standard operational definition for SCD that has consistently been used across epidemiologic studies. Nonetheless, despite differences in populations, study designs, the availability of clinical data, and the operational definitions used to classify SCD, the results of previous epidemiologic studies focusing on potential determinants of SCD typically have been consistent. In CHS, SCD was adjudicated from medical records and interviews with next of kin as to circumstances surrounding the event, and most cases did not have an autopsy and heart rhythm monitoring at the time of the sudden collapse. Misclassification of the outcome is possible and would tend to underestimate the true association. Importantly, the operational definition used to define SCD in this report has been used in multiple previous studies (21,36–42) from CHS, and the findings from these analyses have replicated findings from studies with other operational definitions of SCD. This reflects the fact that each of the operational definitions seek to identify persons who experience a life-threatening arrhythmia, or ventricular fibrillation, that results in SCD in absence of successful resuscitation in the community.

In addition to novel observations, the study has several strengths including prospective design, relatively large population, inclusion of African Americans, long-term follow-up, measures of hsTnT in a central lab, and the adjudication of cardiovascular events by a central committee.

Conclusions

In a large community-based population, there was an association between both baseline and change in cardiac TnT when measured by a highly sensitive assay and SCD risk over long-term follow-up. This association persisted in covariate-adjusted analyses that accounted for demographics, baseline risk factors, and incident heart failure and MI. The findings suggest an association between cardiomyocyte injury in ambulatory subjects and SCD risk beyond that of traditional risk factors.

Appendix

Appendix

For a supplemental table providing further details regarding the included covariates, please see the online version of this article.

Footnotes

This research was supported by the National Heart, Lung, and Blood Institute (NHLBI) contracts HHSN268201200036C, N01-HC-85239, N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01-HC-15103, N01-HC-55222, N01-HC-75150, N01-HC-45133, and NHLBI grant HL080295, with additional contributions from the National Institute of Neurological Disorders and Stroke. Additional support was provided through AG-023629, AG-15928, AG-20098, and AG-027058 from the National Institute on Aging. See also http://www.chs-nhlbi.org. Dr. deFilippi has received honoraria, consulting fees, and grant support from Roche Diagnostics and Siemens Healthcare Diagnostics; and consulting fees and grant support from Critical Diagnostics and BG Medicine. Dr. Dickfeld has received consulting fees and grant support from Biosense Webster; and grant support from General Electric. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

(2011) 2011 ACCF/AHA focused update of the guidelines for the management of patients with unstable angina/ non–ST-elevation myocardial infarction (updating the 2007 guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol57:1920–1959.

Toolbox

Thank you for your interest in spreading the word about JACC: Journal of the American College of CardiologyNOTE: We request your email address only as a reference for the recipient. We do not save email addresses.

Your Email *

Your Name *

Send To *

Enter multiple addresses on separate lines or separate them with commas.